Abstract 374: Targeted Deletion of A2B Adenosine Receptors Attenuates the Protective Effects of Myocardial Postconditioning
Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (PostCon). To assess the hypothesis that A2B adenosine receptor (A2BAR) activation contributes to PostCon-induced protection, global ischemia-reperfusion was performed with and without PostCon or the selective A2B agonist, BAY 60 – 6583 (BAY), in isolated wild-type (WT) and A2BAR knockout (A2BKO) mouse hearts. In WT hearts, PostCon improved post-ischemic recovery of left ventricular developed pressure (LVDP) to 63.3±1.6 % of pre-ischemic baseline vs. 49.9±1.6 % in non-PostCon controls (CTL), lowered end diastolic pressure (EDP) to 15.8±1.5 mmHg vs. 27.9±1.6 mmHg in CTL, and reduced coronary efflux of cardiac troponin I (cTnI) to 2507±359 ng/g heart weight vs. 4693±343 ng/g in CTL (n=12 both groups, p<0.05 each comparison). Treatment with BAY in the first two min of reperfusion mimicked beneficial effects of PostCon in WT hearts (LVDP: 64.7±2.0 % baseline, EDP: 16.2±2.0 mmHg, cTnI: 3311±366; n=13, not significant compared to respective PostCon values). Real-time PCR confirmed absence of A2BAR in A2BKO hearts and demonstrated no changes in expression of other adenosine receptor subtypes compared with WT hearts. In A2BKO hearts, neither PostCon nor BAY improved recovery of LVDP (50.8±1.6 % baseline for CTL vs. 54.5±1.7 % with PostCon vs. 53.0±1.4 with BAY; n=6 each group), and neither affected EDP or release of cTnI. During reperfusion, both PostCon and BAY increased survival kinase signaling through Akt and ERK1/2 phosphorylation in WT but not A2BKO hearts. In non-ischemic WT hearts, Akt and ERK1/2 phosphorylation was increased by both BAY treatment and application of the PostCon stimulus. These data demonstrate that the protective effects of PostCon are attenuated by targeted deletion of A2BAR and are mimicked by selective A2BAR activation, suggesting A2BAR activation is an important trigger leading to PostCon-induced myocardial protection.